Abstract:

Method for the continuous measurement of the glucose concentration in
blood undergoing pulsational flow, with the steps: determination of a
value for the glucose concentration for a first measurement cycle, and
repetition of the determination of this value in subsequent measurement
cycles, where there is multiple detection, within each measurement cycle,
of the transmittance and/or scattering power of the blood for at least
two incident MR wavelengths, calculation of an indicator value depending
on the blood glucose concentration, and ascertaining the blood glucose
concentration by comparing the indicator value with a previously
determined calibration table, determination of the blood temperature
during the detection of the transmittance and/or scattering power,
continuous measurement of the pulse duration of the pulsational blood
flow, where the duration of the measurement cycle is arranged to keep in
step as integral multiple of the pulse duration, where the first of the
at least two MR wavelengths is selected from the wavelength range
1560-1630 nm, and the second of the at least two MR wavelengths is
selected from the wavelength range 790-815 nm, and the ratio of the
transmittance and/or scattering power of the at least two wavelengths is
calculated, this ratio serving in relation to the blood temperature as
indicator value for reading off the blood glucose concentration from the
calibration table.

Claims:

1. A method for the continuous measurement of glucose level in blood
undergoing pulsing flow, the method comprising the steps:determining a
value for the glucose level for a first measurement cycle;repeating the
determination of this value in subsequent measurement cycles such that
there is multiple detection within each measurement cycle of the
transmission or scattering power of the blood for at least to two
incident NIR wavelengths, calculation of an indicator value dependent on
the blood-glucose level and ascertaining the blood-glucose level by
comparing the indicator value with a previously determined calibration
table;determining the blood temperature during the detection of the
transmission and/or scattering power,continuously measuring the pulse
duration of the pulsing blood flow, the duration of the measurement cycle
being set to keep in step as integral multiple of the pulse
duration,selecting the first of the at least two NIR wavelengths from the
wavelength range 1560-1630 nm, and the second of the at least two NIR
wavelengths from the wavelength range 790-815 nm, andusing the ratio of
the transmission or scattering power of the at least two wavelengths
being calculated with this ratio relative to the blood temperature as an
indicator value for reading off the blood-glucose level from the
calibration table.

2. The method according to claim 1 wherein the at least two NIR
wavelengths are irradiated in an amplitude-modulated manner with
modulation frequencies above 1 MHz.

3. The method according to claim 1 wherein the measurement cycle covers
nonoverlapping time windows of the same length, in which in each case the
same number of measurement values is recorded for transmission and/or
scattering power of the blood, wherein an ensemble average over all of
the time windows of the measurement cycle takes place in order at the end
of the measurement cycle to have calculated a determined time window
containing the number of average measured values.

4. The method according to claim 3 wherein each time window comprises less
than 100 milliseconds.

5. The method according to claim 3 wherein the number of the measured
values for transmission and/or scattering power of the blood in each time
window is at least 10,000.

6. The method according to claim 3 wherein the average measured values in
the determined time window are subjected to a Fourier transformation in
the frequency range.

7. The method according to claim 6 wherein the Fourier components of the
average measured values for modulation frequency of the amplitude
modulation of the irradiated NIR wavelengths is evaluated as a gauge for
the transmission or scattering power of the blood.

8. The method according to claim 6 wherein an integral in the frequency
range over the Fourier components of the average measured values at an
interval around the modulation frequency of the amplitude modulation of
the irradiated NIR wavelengths is evaluated as a gauge of the
transmission or scattering power of the blood.

9. The method according to claim 1 wherein the adjustment kept in step of
the duration of the measurement cycle to the continuously recorded pulse
duration of the blood is carried out sing a variable number of time
windows with fixed duration and adding a variable measurement dead time,
wherein the number of the time windows and the measurement dead time are
calculated in step.

10. An apparatus for carrying out the method according to claim 1 wherein
the blood is taken from a living organism in a circulation, measured and
returned, the apparatus further comprising:a measuring cell embodied for
the continuous inflow and outflow of blood with a trans-illumination zone
embodied in a flattened manner,at least two NIR light sources arranged on
a flat side of the measuring cell for trans-illuminating the measuring
cell in the direction toward the opposite flat side,at least one NIR
detector arranged on the flat side, which lies opposite that with the NIR
light sources andmeans for measuring the blood temperature at least in
the trans-illumination area of the measuring cell.

11. The apparatus according to claim 10, further comprisingan NIR laser
with beam splitter and frequency doubling medium, which at the same time
emits NIR light with 1560-1630 nm wavelength as well as NIR light with
half the wavelength to show the at least two NIR light sources.

Description:

[0001]The invention relates to a method for contact-free blood-sugar
metering by means of NIR (near infrared) spectrometry in flowing, pulsing
blood, which in particular is first removed from a living organism and
returned again after a treatment, e.g. dialysis. The invention also
relates to an apparatus that as an additional or integral component of a
dialysis apparatus is suitable for monitoring the blood sugar content.
Furthermore, the invention is applicable in the noninvasive in vivo
blood-sugar level monitoring.

[0002]The determination of the blood-sugar level without direct contact
with the blood, in particular without a special withdrawal of blood for
this purpose, has been the subject of intensive medical research and
development for more than two decades. The main objective thereby is the
provision of a compact portable measuring apparatus for diabetics, which
ideally can quickly provide reliable sugar values at the most through
skin contact and without injuring the skin. Despite considerable efforts
by numerous researchers, which have produced a large number of
interesting approaches to a solution, to date no satisfactory measuring
apparatus of this type has reached market readiness.

[0003]The prior art, which at this point can be cited only in extracts,
deals both with in vivo as well as in vitro measurement, where very often
a transfer is made directly from experimental in vitro results to the in
vivo case. However, a transfer of this kind is in principle untenable,
since it does not take into consideration at all or only incompletely the
considerable complications of the interactions of all blood constituents
and the solid tissue with light.

[0004]Thus, for example, in reality the proposal sometimes made of the
analysis of the NIR light scattered back from the living body is a
problem per se in a class of its own, in which the informative value of
the scattered light is firstly questionable. Since scattered photons
follow a nonlinear path, influenced by multiple scattering, back to the
surface of the body, it must be decided at the detector which portion of
light has run through a blood vessel at all and thus has information
about the blood-sugar level. Such a source localization by itself is
technically complex and is described, e.g. in DE 103 11 408[7,251,518].

[0005]Some sources therefore dedicate themselves primarily to the question
of the physical measured variable that is to be used for glucose
metering. The metrological details that an in vivo measurement would
actually require are, in contrast, simply assumed to be technically
soluble.

[0006]Thus, for example, U.S. Pat. No. 5,009,230 proposes measuring the
change of the polarization of linearly polarized IR light when passing
through perfused tissue, in concrete terms the rotation of the
polarization plane by glucose molecules. The measurable light intensity
behind a polarization filter is used to determine the concentration. It
is thereby considered important for the sensitivity to change
periodically between polarization directions perpendicular to one
another.

[0007]It is known from U.S. Pat. No. 5,222,496 that the intensity of
transmitted or reflected NIR light is to be placed in proportion to one
another for several wavelengths in order to measure the glucose level. In
particular light around 1600 nm wavelength is used, which is absorbed
particularly well by glucose due to molecular fluctuations. In contrast,
for this wavelength range water has a local absorption minimum. In order
to compensate for the signals of other blood constituents, as well as the
influence of the surrounding tissue or, for example, the pigmentation of
the skin with the in vivo measurement, U.S. Pat. No. 5,222,496 suggests
the additional use of at least one further wavelength in the vicinity of
the first, which in turn is not to be absorbed by glucose. Particular
importance is attached to the slight difference of the wavelengths--less
than 300 nm, preferably 60 nm--in order to ensure the same is type of
scatter behavior.

[0008]However, both sources are not concerned at all, for example, with
the movement of the blood in the living organism. Also the knowledge of
the temperature of the blood, doubtlessly necessary for spectrometric
analysis, is referred to only briefly in U.S. Pat. No. 5,009,230, but by
no means dealt with.

[0009]It is presumably due to the obviously immense complexity of the
measurement task that indirect methods for determining blood sugar are
also repeatedly proposed. Photoacoustic measurement is cited by way of
example here, in which living tissue is irradiated with different
wavelengths in order to detect the thermal expansion during the
absorption of the radiation in the form of detectable ultrasonic waves on
the skin's surface, see, e.g. U.S. Pat. No. 6,484,044. The wavelengths
are also selected hereby according to the known absorption maximums of
glucose, and likewise differential measurements are carried out for the
purpose of signal isolation.

[0010]However, the fundamental problem of complexity is thus by no means
circumvented, let alone solved. As already with the backscatter of
photons, here too the information content of the sound signals is
uncertain, their precise source localization unclear and their formation
certainly influenced by numerous highly individual and possibly even
changeable tissue parameters. The photoacoustic method is ultimately a
highly empirical method, which evidently has difficulty finding a
standard calibration for broad applicability.

[0011]In conclusion, the GlucoWatch® method should be referenced as
prior art, which is the only one on the market so far with FDA approval.
GlucoWatch® indeed does not require a blood sample for analysis, but
is attached to the skin of the wearer such that it can take up fluid
through the skin. Users have frequently reported skin irritations and,
furthermore, even the manufacturer advises against using GlucoWatch®
as the only means of judging the correct insulin dosage.

[0012]The applicant believes a method for noninvasive blood glucose
measurement will generally not be able to do without empirical data
interpretation. However, this should remain limited in the interest of
the most universal possible applicability of a system of this type to
partial areas of the method that can be monitored well.

[0013]The following objects must be attained in order to create a
noninvasive system: [0014]1. Blood-sugar metering in flowing, pulsing
blood (in vitro) recording empirical, largely universal calibration
curves, [0015]2. Transferring the method from the in vitro structure to
preferably large blood vessels (e.g. aorta) by [0016]a. Source
localization, elimination of signals without information, [0017]b.
Compensation for tissue and skin influences on the remaining signal,
[0018]c. In situ temperature determination in the blood vessel and
interstitial tissue for application of the calibration curves.

[0019]Considerable preliminary work has already been published by the
applicant re points 2a and 2b in DE 103 11 408. The object 2c is the
subject matter of future work and will be submitted in a separate
application in due course. The present application deals solely with
object 1. U.S. Pat. No. 5,222,496 is deemed to be the closest pertinent
prior art in this case.

[0020]The in vitro determination of the blood-glucose level is of interest
per se for integration into dialysis equipment. Studies in the US show
the importance of the continuous monitoring above all in the case of
dialysis patients with diabetes. In the absence of suitable apparatuses,
cases of death have already been recorded.

[0021]The object of the invention is therefore to provide a method and an
apparatus for the contact-free measurement of blood-glucose level in
flowing pulsing blood.

[0022]The object is attained through the method with the features of the
main claim. The subordinate claims disclose advantageous embodiments and
an apparatus for carrying out the method.

[0023]The invention described below is based on the realization that the
scatter behavior of the flowing pulsing blood for NIR light (measurement
light) has a dominant influence on transmitted and/or scattered
measurement light intensities.

[0024]The light scattering in a blood sample at rest is already very
marked by the blood substances present therein (such as lipid, alcohol,
etc.), but also by the number and shape of the scatter particles present
in the blood plasma--in particular red and white blood corpuscles that do
not have a spherical form. Even in blood at rest these particles move
with respect to one another, rotate their relative position and cause a
continuous change in the anisotropic scattering power. The intrinsic
movement of the scatter particles is related to the temperature of the
blood sample. Furthermore, the NIR absorptive capacity of water is also
dependent on the temperature.

[0025]It is therefore a first feature of the invention to determine the
blood temperature through a separate measurement, where at least a
precision of 0.5° C., preferably even 0.1° C. or better
must be achieved.

[0026]In order to prevent the intensity of the transmitted or
backscattered measurement light from being susceptible to particle-based
scattering, it was found that a statistical averaging of the measured
values must be carried out via a plurality of successive time windows.
The time windows should thereby preferably each be a few milliseconds,
but no more than 100 ms long, and in their entirety (comprising a
sequence of nonoverlapping time windows, referred to below as a
measurement cycle) cover a time period of at least one second, preferably
2-3 seconds. Thus at least 10, but preferably 200 or more, discrete time
windows are available for the evaluation.

[0027]Within each of the time windows, furthermore, at least 10,000
discrete measured values are to be recorded, preferably as many as
30,000. The measured values within the time window therefore cover
intensity fluctuations on the microsecond scale. This scale is not
relevant for the spontaneous movement of the blood, i.e. the blood is
quasi static. It is used instead to separate the light signals (see
below).

[0028]According to the invention the at least 10,000 measured values
recorded per time window are registered by a process control computer
(e.g. PC with data acquisition card) and stored in an array. The measured
values of the following time window are recorded in the same number and
added to the same array. The stored measured values thus grow in a
cumulative manner with each further time window until the measurement
cycle ends (at least 10 time windows, minimum measurement duration 1
second). Subsequently, the accumulated measured value array can be
divided by the number of contributing time windows for normalization.
However, normalization is not obligatory, since measurement ratios are
used in the further process.

[0029]For a blood sample at rest, this procedure is sufficient to
eliminate the influences of the movement of scattering particles in the
blood by averaging. For the measured values recorded in an individual
time window an ensemble average is thus carried out over all the movement
conditions of the blood. Nevertheless, the extent of the particle
movement in the blood plasma is determining for the effective average
scattering strength of the sample. The scattering strength variability is
leveled by the ensemble average, but not absolutely determined. For this
reason alone, the temperature measurement is also necessary.

[0030]When the blood flows in pulses manner during the measurement,
further movement conditions of the blood take place, which essentially
are periodically repeated with the pulse frequency. The blood is in
particular subjected to pressure fluctuations and will have additional
turbulences and differences in density. Therefore according to the
invention the ensemble average--and thus the length of the measurement
cycle--is extended over at least one complete pulse duration. In the case
of a healthy adult when awake, the pulse frequency is approximately 1 Hz,
so that this is easily possible within the above-referenced specification
of the measurement cycle of 2 to 3 seconds. According to the invention
the measurement cycle is adjusted as precisely as possible to an integral
multiple of the pulse duration in order to take into account each
recurring movement condition of the blood with the same weight in the
ensemble average.

[0031]The pulse frequency on the one hand can thereby be recorded
separately by sensors and transmitted to the process control computer so
that it continuously calculates anew the number and length of the
individual time windows and actuates the data acquisition unit
accordingly. However, it is generally even possible to conclude the pulse
frequency directly from the recorded measured values. To this end, the
ensemble average outlined above is first carried out with the
specification of a hypothetical pulse frequency and then optimized with
the variation of the pulse frequency as fit parameter.

[0032]For optimization, for example, the integrated measurement signal can
serve as characteristic value over the individual time window after
ensemble average (the at least 10,000 cumulated measured values), which
is a gauge for the overall scattering strength of the blood. Although the
latter is dependent on temperature, over the short time period of
successive measurement cycles (several times 2-3 seconds), the
temperature can be assumed to be virtually constant. If the ensemble of
blood movement conditions is selected unfavorably with respect to the
pulse duration, the characteristic value will show clear variations
between consecutive measurements. The optimality criterion is here the
minimization of these variations.

[0033]Certainly other measurement and/or calculation methods for the pulse
duration can be found and used. According to the invention it is
important here to take into account the pulse duration in the
establishment of the time window and the measurement cycle for the
statistical evaluation. Furthermore, it can be advantageous to work with
fixedly selected time windows of a maximum of 100 ms, so that it is not
possible here to scan the entire pulse exactly with an entire number of
time windows. In this case, the introduction of a measurement dead time
is recommended, generally less than the fixed time window in order to
establish the desired synchronicity with the pulse. Measurement dead time
means that measured values of the light detectors are not considered or
are not generated at all during this period. The measurement dead time
can as described above also be dynamically optimized.

[0034]Preferably the measurement cycle is extended over a plurality of
pulses. However, this plurality is typically a small number (<10),
since a measured value must be available within a few seconds. This is
particularly important for an in vivo system, in which the user has to
carry out the measurement himself. Longer measurement durations are a
reason for movement artifacts.

[0035]For the spectrometric determination of the blood-glucose level in
part U.S. Pat. No. 5,222,496 is now followed, in that an NIR wavelength
from the range 1560-1630, preferably 1600 nm is irradiated into the
blood. Basically transmission and/or scattering strength of the blood can
be measured for the selected wavelengths and used as an indicator for the
blood-glucose level.

[0036]With in vitro measurement, preferably the transmission of irradiated
light is recorded in order to measure the extinction coefficient (also:
optical density). This is defined as the negative decadic logarithm of
the ratio of the transmitted to the irradiated light intensity. It is
calculated from the at least 10,000 measured values of the determined
time window after the ensemble average.

[0037]In the determination of the extinction coefficient it should be
noted that the IR light detector can also record undesired light portions
that falsify the data. Although it is possible to use different detectors
with different chromatic sensitivity, these too register extraneous light
in their respective sensitive wavelength range. Therefore the irradiated
light is preferably amplitude-modulated with a modulation frequency of at
least 1 MHz, particularly preferably 3-4 MHz. This amplitude modulation
in the at least 10,000 measured values within the time window lasting a
maximum of 100 ms is in principle resolvable and permits the spectrum
analysis of the data in the time window. A spectral representation of the
measured values of the time window after the ensemble average is
calculated preferably by means of fast Fourier transformation. In the
further evaluation then only Fourier components from the range of the
modulation frequency are included. This way in the simplest case the
Fourier components can be determined for modulation frequency alone
optionally through interpolation and assumed as a gauge for the
transmitted intensity. However, it has proven to be advantageous instead
to use a numerical integral over the Fourier spectrum in the frequency
range, wherein values are added in a window having the width 2 Δf.
The modulation frequency thereby lies centrally in the integration
window. The value Δf should be selected to be as small as possible
but sufficiently large to compensate for fluctuations between consecutive
measurements (at intervals of a few seconds) between which the physical
variable to be measured cannot have changed substantially. This is
therefore a fit parameter that automatically varies during the
measurement and can be adjusted. Preferably it is at some time stored as
a constant in the evaluation unit and used again for later measurements.
Of course, it can be checked from time to time and readjusted.

[0038]Unmodulated extraneous light is virtually eliminated after the
above. The irradiated intensity, however, scales with the laser power and
is known. The extinction coefficient can thus be given as defined above

[0039]The extinction coefficient E, as described above, depends on the
movement conditions of the blood, but also simply on the composition of
the blood particles, in particular with respect to type and number, that
is, on the hematocrit values, which can differ substantially among
different people. Furthermore, the fat level in the blood plays a role,
which can vary even hour by hour in the same person.

[0040]For compensation, therefore, at the same time a second NIR
wavelength is irradiated, the transmission of which depends only on
hematocrit values and fat content, but not on other factors such as blood
sugar or, e.g. the oxygen saturation of the blood. For this the
"isobestic" wavelength lends itself at approximately 808 nm in
particular, for which the absorptive capacity of oxyhemoglobin and
deoxyhemoglobin is known as identical. It lies at the same time in the
extended absorption minimum of water. Here the approach according to the
invention already differs significantly from the teaching of U.S. Pat.
No. 5,222,496.

[0041]Basically, variations of the cited wavelengths are possible, i.e.
also values in the vicinity of 808 nm (probably in the range of 790-815
nm) can be considered. Since the light preferably is irradiated from
laser diodes, it can here be considered as a technically very
advantageous embodiment instead of two lasers to use only a single one
with a frequency doubler and beam splitter. This can be used to place the
irradiated intensities of the different wavelengths in a fixed ratio to
one another in principle independent of pump capacity and laser control.

[0042]For the isobestic wavelength, the extinction coefficient EISO is
measured. The ratio R=E/EISO is determined in the process control
computer and the blood-sugar level can be read off based on the
calibration function K (R, T) available as a table in the computer. The
value T is thus the blood temperature to be measured at the same time,
which in the simplest case is to be detected in the in vitro measurement
by means of a temperature sensor. It is not necessary to bring the sensor
into direct contact with the blood, but it can be installed on the
outside on a measuring cell. Furthermore, there is also the possibility
of detecting the temperature via the infrared irradiation emitted by the
blood, when the NIR laser sources are temporarily switched off (e.g.
during the above-referenced measurement dead time, at least one IR
detector is available anyway).

[0043]The calibration table K (R, T) is to be determined on the one hand
in that NIR measurement values are determined with blood glucose data
from other measurement processes, for example, by means of measurement
strips.

[0044]A concrete illustrated embodiment is given below for a system for in
vitro blood-sugar metering and the results of a few exemplary
measurements are presented. This is supported by the following figures:

[0045]FIG. 1 shows a structural sketch of the apparatus for carrying out
the method described here;

[0046]FIG. 2 compares the spectrometrically measured blood sugar values
with those of a simultaneous measurement by means of blood sugar test
strip according to the prior art.

[0047]FIG. 1 shows in the upper area of the image the side view of a
measuring cell, where on one side (in this case, that turned toward the
viewer) two laser light sources 10 and 14 as well as a temperature sensor
12 are arranged. The laser light sources 10 and 14 are preferably the
exit ends of optical fibers, but can also be laser diodes that have an
electric supply in situ. In the laboratory experiment shown below,
tunable laser sources of the type High Performance Tunable Laser TSL-510
are used, which, however, for reasons of cost alone is not intended to be
a preferred embodiment of the invention. The irradiation power in the
apparatus described here should preferably be 10 mW.

[0048]The temperature sensor 12 measures the outside temperature of the
cell. This can easily be used by one-time calibration to determine the
blood temperature. However, it should be ensured that the measuring cell
is insulated very well with the temperature sensor 12 from temperature
fluctuations. Otherwise, even the opening of a window could lead to
incorrect measurements.

[0049]A measuring cell that, for example, is integrated into the feed
lines of a dialysis apparatus should comprise a material permeable to NIR
light (e.g. quartz glass, CIR-Chalcogenide IR-Glass) and typically has in
the area of the connections to the feed lines a circular cross section of
D=4.2-4.5 mm diameter (cf. FIG. 1) In the trans-illumination zone the
diameter in the irradiation direction must be reduced to approximately
d=2. FIG. 1 below shows a cross-sectional representation, where a clamp
20 is used to hold the flattened measuring cell. Likewise shown are the
laser sources 10 and 14 and the temperature sensor 12 on the one side of
the measuring cell. On the opposite side of the measuring cell at least
one NIR detector 16 is arranged that measures the transmitted radiation.
Concretely, an NFI-2053-FC-M 10 MHz InGaAs photoreceiver was used. An NIR
laser is preferred with beam splitter and frequency doubling medium which
at the same time emits NIR light at 1560-1630 nm wavelength as well as
NIR light with half the wavelength to show the at least two NIR light
sources.

[0050]FIG. 1 finally also shows a computer-supported data acquisition and
evaluation unit 18 as well as a display of the determined values for the
blood-glucose level. Here for example the high-speed data acquisition
card WA1-100-110 from Acquitec with a scanning rate of 20 MHz and a
resolution of 12 Bit, as well as an AcquiFlex oscilloscope, waveform
editor and logic analyzer software are recommended. The apparatus
operates as described above and now permits the continuous monitoring of
the blood.

[0051]FIG. 2 illustrates based on some exemplary measurements of human
blood that the calibration necessary for using the apparatus and the
method according to the invention can be determined. To this end first
reference values (e.g. with the commercial Accu-Chek® blood-sugar
metering apparatus, but better with much more precise analysis methods)
is determined on test subjects. On the abscissa the "true" blood sugar
values are entered in units mg/dl and the ordinate shows the logarithm of
the intensity ratio R, as it is determined with the method described
above on blood samples taken by the doctor from the same test subjects.
Evidently the "true" values--although they can also still exhibit errors
themselves--are arranged approximately along a trend line. This trend
line can be used as a calibration curve for converting the spectrometric
values--if the blood temperature is known.

[0052]FIG. 2 shows only preliminary initial results. The calibration
curves are to be determined for a plurality of blood temperatures and of
course with a much greater number of blood samples.